Since the results of our in vitro and detailed in vivo studies on the metal-L-DOPA chelates were found to be very consistent with the metal chelation approach for improved replenishment of dopaminergic pools of rat brain, it is considered very worthwhile and important to undertake further interdisciplinary research that is necessary for developing L-DOPA-chelate systems suitable for clinical studies. The proposed research consists of biological and physicochemical (and biophysical) phases. The biological phase will involve (1) a detailed in vivo exploration of the transport and metabolism of a few selected metal-L-DOPA ternary chelates (other than Cu(II)-L-DOPA-ATP), (2) the therapeutic potency and efficacy of the chelates using animal models, (3) investigation of the oral mode of treatment and examination of the discrete brain nuclei, (4) in vitro studies on the mode of activity of DOPA decarboxylase on the chelates, (5) physiological disposition of the L-DOPA-chelate-bound metals and (6) toxicological characteristics of the chelate treatment. The physicochemical and biophysical studies include (1) synthesis and characterization of the promising chelates, (2) determination of their instability characteristics if any, and develop procedures for their stabilization suitable for storage and biological application and (3) mode and extent of interaction of DOPA-decarboxylase and its coenzyme with the metal-L-DOPA chelates. Based on the biological, biophysical and physicochemical studies, the mode of activity of the chelates in the peripheral and cerebral areas will be determined and one or more metal-L-DOPA chelates will be selected and recommended for clinical testing.